Therapy In Postmenopausal Women Research Articles

Measurements of Bone Health after Thyroid-Stimulating Suppression Therapy in Postmenopausal Women with Differentiated Thyroid Carcinoma: Bone Mineral Density versus the Trabecular Bone Score

Background: Thyroid-stimulating hormone (TSH) suppression therapy is an important treatment modality for differentiated thyroid carcinoma (DTC), but it increases fracture risk. The aim of this study was to evaluate changes in bone mineral density (BMD) and trabecular bone score (TBS) in postmenopausal DTC patients receiving TSH suppression therapy. Methods: A total of 410 postmenopausal DTC patients who underwent thyroidectomy and had at least two dual-energy X-ray absorptiometry measurements, including a preoperative measurement, were included. Patients who had osteoporosis medication for more than 1 year were classified as ‘patients with osteoporosis’. Results: In patients without osteoporosis, the change in %BMD was similar between TSH suppression (−) and (+) groups, while the decrease in %TBS was significantly greater in the TSH suppression (+) group than that of the TSH suppression (−) group. The relative risk of vertebral fracture was decreased by TBS changes but not by BMD changes. In patients with osteoporosis, both BMD and TBS showed significant increases in the TSH suppression (−) group but not in TSH suppression (+) group. At year 4, TBS was significantly lower in the TSH suppression (+) group than that in the TSH suppression (−) group, while BMD showed no difference between groups. Conclusions: TBS may better reflect bone health than BMD in postmenopausal DTC patients with TSH suppression therapy.

From Theory to Practice: Bone Health in Women with Early Breast Cancer Treated with Aromatase Inhibitors.

Aromatase inhibitors (AI) are extensively used as adjuvant endocrine therapy in post-menopausal women with hormone receptor-positive early breast cancer (HR+ EBC), but their impact on bone health is not negligible. This work aimed to assess bone loss, fracture incidence, and risk factors associated with these events, as well as the prognostic influence of fractures. We have conducted a retrospective cohort study of women with HR+ EBC under adjuvant therapy with AI, during a 3-year period. Four-hundred-and-fifty-one eligible women were reviewed (median age 68 years). Median time under AI was 40 months. A fracture event occurred in 8.4%, mostly in the radium and femoral neck and in older women (mean 74 vs. 68 years, p = 0.006). Age (OR 1.01, 95% CI 1.01–1.07, p = 0.024) and time under AI (OR 1.02, 95% CI 1.00–1.04, p = 0.037) were independent predictors of fracture, with a fair discrimination (AUC 0.71). Analysis of disease-free survival according to fracture event varied between groups, disfavoring the fracture cohort (at 73 months, survival 78.6%, 95% CI, 47.6–92.4 vs. 95.6%, 95% CI, 91.2–97.8, p = 0.027). The multivariate model confirmed the prognostic impact of fracture occurrence (adjusted HR of 3.17, 95% CI 1.10–9.11; p = 0.032). Bone health is often forgotten, despite its great impact in survivorship. Our results validate the pathophysiologic link between EBC and bone metabolism, which translates into EBC recurrence. Further research in this area may help refine these findings. Moreover, early identification of women at higher risk for fractures is warranted.

Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1

Abstract Background SERDs belong to a class of ER-targeted therapies that antagonize and degrade ERs, including in ER-dependent tumors resistant to other endocrine therapies (ET). This study (AMEERA-1; NCT03284957) investigates SAR439859, an oral SERD, as monotherapy and (in ongoing cohorts) in combination with targeted therapies in patients (pts) with ER+/HER2- mBC. Here we report updated safety and antitumor activity with SAR439859 monotherapy, including exploratory analyses by prior therapy and ESR1 status. Methods This open-label, phase 1/2, first-in-human study assessed SAR439859 as monotherapy in Parts A (dose escalation 20-600 mg once daily [QD]) and B (dose expansion with recommended dose at 400 mg QD). Eligible pts were heavily pre-treated, postmenopausal women with ER+/HER2- mBC and measurable disease who received ≥6 months of prior ET in the advanced setting. Prior chemotherapy, mammalian target of rapamycin inhibitors (mTORi) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for advanced disease were allowed. This analysis pooled data from pts receiving SAR439859 ≥150 mg (Part A) and 400 mg (Part B), administered in 28-day cycles. Antitumor activity was assessed by the objective response rate and clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] ≥24 weeks) per RECIST v1.1, determined by investigators. Analyses by prior therapy and baseline ESR1 mutation status were performed. Safety was also evaluated. Results Pts (n = 62; Part A: 13; Part B: 49) had a median age of 63 (range 37-88) years and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral metastases. Pts had a median of 2 (range 1-8) prior lines of therapy in the advanced setting (48.4% had ≥3 prior lines): all had prior ET and 72.6% had prior targeted therapy. SAR439859 monotherapy showed antitumor activity in the response-evaluable population (n = 59) and in subset populations with ≤3 prior lines (n = 33) or without prior mTORi, CDK4/6i, or SERD (n = 14) (Table 1). For pts with ESR1 status (n = 58), CBR with SAR439859 was comparable in ESR1 wild-type (36.7%) and mutant mBC (32.1%), with similar results in subpopulations. Treatment-related adverse events (TRAEs) occurred in 62.9% of pts (all grade 1-2); none resulted in SAR439859 discontinuation. Most frequent TRAEs were hot flush (16.1%); constipation and arthralgia (each 9.7%); decreased appetite, vomiting, diarrhea and nausea (each 8.1%); and fatigue (6.5%). Conclusions Among heavily pre-treated pts, SAR439859 demonstrated antitumor activity, similar to historical single-agent fulvestrant activity in less heavily pre-treated pts with advanced/mBC (2L+ setting; no prior targeted agents) (indirect comparison). In both subsets of pts with fewer prior advanced lines of therapy, SAR439859 showed trends of greater clinical activity versus historical fulvestrant activity. SAR439859 had a favorable safety profile with limited TRAEs. No safety signals of cardiac or ocular toxicities were observed. Ongoing parts of the study are investigating SAR439859 in combination with targeted therapies. Based on the monotherapy results, a randomized phase 2 study is investigating SAR439859 compared with physician’s choice in a 2L+ setting (AMEERA-3; NCT04059484). Funding: Sanofi. Antitumor activity overall and in subpopulations by prior lines of therapy (Parts A+B)Overall population (A+B)≤3 Prior advanced linesWithout prior targeted therapy(n = 59)a(n = 33)b(n = 14)cBOR, n (%)–CR000–PR5 (8.5)5 (15.2)3 (21.4)–SD24 (40.7)15 (45.5)8 (57.1)–PD30 (50.8)13 (39.4)3 (21.4)ORR, n (%)5 (8.5)5 (15.2)3 (21.4)CBR, n (%)20 (33.9)14 (42.4)9 (64.3)aPooled cohort (A ≥150 mg QD + B);bSubset of pooled cohort with ≤3 prior lines in the metastatic setting, including ≤1 of either prior chemotherapy or CDK4/6i and no prior mTORi; cSubset of pooled cohort with no prior mTORi, CDK4/6i, or fulvestrant.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Citation Format: Hannah M Linden, Mario Campone, Aditya Bardia, Gary A Ulaner, Alice Gosselin, Séverine Doroumian, Vasiliki Pelekanou, Marina Celanovic, Sarat Chandarlapaty. A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-08.

Abstract PS12-27: From theory to practice: Impact of aromatase inhibitors in the bone health of women with early breast cancer

Abstract Background: Aromatase inhibitors (AI) are extensively used as adjuvant endocrine therapy in post-menopausal women with hormone receptor positive early breast cancer (HR+ EBC), but their impact on bone health is not negligible. They decrease bone mineral density, accelerate osteoporosis and lead to increased risk of fractures, thus impairing quality of life. Identification of patients at higher risk would be helpful for best treatment decisions. Recommendations have been published for bone health preservation but real-world data regarding implementation and adherence to these recommendations is scarce. This work aimed to assess bone loss, fracture incidence and risk factors associated with these events, as well as the prognostic influence of fractures in women undertaking adjuvant AI. Materials and Methods: In this retrospective cohort study, we have evaluated women with HR+ EBC under adjuvant therapy with AI, during a 3-year period. A minimum of 3 months under AI and 3 years of follow-up after AI start were necessary for inclusion. Statistical analysis of collected data was performed using R 3.5.2, R-Studio 1.1.456 and Stata 15.1 software. Results: 451 eligible women were reviewed (median age 68 years, 30-98 min-max). Median time under AI was 40 months (3-114). Baseline bone densitometry, carried out in only 69% patients, showed abnormal results in 75%, but only 69% and 16% started calcium/vitD supplementation and bisphosphonates therapy, respectively. A fracture event occurred in 8.4%, mostly in the radium and femoral neck and in women with higher age (p=0.006). This group also showed lower T-scores at lumbar spine and femoral neck (p=0.067). On multivariate analysis, age (OR 1.04, 95% CI 1.01-1.07, p=0.016) and time under AI (OR 1.02, 95% CI 1.00-1.03, p=0.045) were independent predictors of fracture events, with a fair discrimination (AUC 0.71). Analysis of disease-free survival according to fracture event varied between groups disfavouring the fracture cohort (at 73 months, survival 78.6%, 95% CI, 47.6-92.4 vs. 95.6%, 95% CI, 91.2-97.8, p=0.027). The multivariate model confirmed the prognostic impact of fracture occurrence (adjusted-HR of 3.17, 95% CI 1.10-9.11; p=0.032). Conclusion: Bone health is often forgotten, despite its great impact in survivorship. Our results suggest a pathophysiologic link between EBC and bone metabolism, potentially estrogen-mediated, which translates into EBC recurrence. Further research in this area may help refining these findings. Moreover, early identification of women at higher risk with individualized treatment plans comprising shorter duration of AI is warranted. Poor adherence to existing guidelines is a crucial barrier to effective approaches to bone health. Citation Format: Leonor Vasconcelos Matos, Maria Teresa Neves, Fatima Alves, Mafalda Baleiras, André Ferreira, Pedro Cotovio, Tiago Dias Domingues, Mariana Malheiro, Joana Graça, Leonor Fernandes, Ana Plácido, Helena Miranda, Ana Martins. From theory to practice: Impact of aromatase inhibitors in the bone health of women with early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-27.

Meta-analyses of phase 3 randomised controlled trials of third generation aromatase inhibitors versus tamoxifen as first-line endocrine therapy in postmenopausal women with hormone receptor-positive advanced breast cancer.

Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression-free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8% and 55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. Anonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. The OR for clinical benefit rate was 1.56, in favour of AIs (p<0.001). The duration of clinical benefit was not significantly increased by AIs (HzR0·88; p=0.08). For PFS the HzR (0.82) was in favour of AIs (p=0·007). However, for OS the HzR (1.05) was not significantly different between AIs and tamoxifen (p=0.42). Although third generation AIs put significantly more patients into 'clinical benefit', their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.

Enzyme-linked immunosorbent assay using fragment antigen-binding (Fab) antibody for determination of deoxymiroestrol, a potent phytoestrogen from Pueraria candollei

ABSTRACTDeoxymiroestrol is the most potent phytoestrogen in the chromene group found in Pueraria candollei. The estrogenic activity of P. candollei, functions as hormone replacement therapy in postmenopausal women. This study established an enzyme-linked immunosorbent assay (ELISA) for quantifying deoxymiroestrol using fragment antigen-binding (Fab) antibody to improve analytical performance. Our ELISA specifically detected deoxymiroestrol in the range of 31.25–1,000 ng/mL. Intra- and inter-assay precision was 1.48%–7.11% and 0.58%–9.31%, respectively, the recovery of authentic deoxymiroestrol spiked into samples was 99.77%–101.61%, and the limit of detection was 30.80 ng/mL. The findings of P. candollei root bark determined using our developed ELISA with Fab antibody and an ELISA with anti-deoxymiroestrol polyclonal antibody were consistent (R2 = 0.9807). The developed ELISA can be applied to the quality control of deoxymiroestrol derived from P. candollei.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases

A systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies was conducted to assess the association between menopausal hormone therapy and cardiovascular disease. The PubMed and EMBASE databases were searched for articles published from 2000 to 2019, using review methods based on a previous Cochrane review. Quality assessment of RCTs and observational studies was conducted using the Jadad scale and the Newcastle–Ottawa Scale, respectively. A total of 26 RCTs and 47 observational studies were identified. The study populations in the RCTs were older and had more underlying diseases than those in the observational studies. Increased risks of venous thromboembolism [summary estimate (SE), 95% confidence interval (CI): RCTs, 1.70, 1.33–2.16; observational studies, 1.32, 1.13–1.54] were consistently identified in both study types, whereas an increased risk of stroke in RCTs (SE: 1.14, 95% CI: 1.04–1.25) and a decreased risk of myocardial infarction in observational studies (SE: 0.79, 95% CI: 0.75–0.84) were observed. Differential clinical effects depending on timing of initiation, underlying disease, regimen type, and route of administration were identified through subgroup analyses. These findings suggest that underlying disease and timing of initiation should be carefully considered before starting therapy in postmenopausal women.

The Impact of Premature Menopause on Future Risk of Cardiovascular Disease

Cardiovascular disease remains the leading cause of morbidity and mortality for women in the USA. Recent multi-society guideline updates endorse using a history of premature menopause, defined as occurring before age 40 years, as a risk-enhancing factor for atherosclerotic cardiovascular disease risk assessment in women. Here, we review recent literature on cardiovascular disease risk in women with premature menopause, possible mechanisms linking premature menopause to cardiovascular disease, and the role of menopausal hormone therapy in postmenopausal women. Large cohort studies and meta-analyses have demonstrated significant associations between premature menopause and development of diverse cardiovascular diseases. In addition to atherosclerotic cardiovascular disease, recent studies have noted accelerated development of valvular heart disease and venous thromboembolism. Surgical premature menopause may be associated with greater risk of cardiovascular disease compared with natural premature menopause; further research to clarify differential risk and relevant underlying mechanisms is needed. Although the cardiovascular risks of menopausal hormone therapy appear largely restricted to women over age 60 years and more than 10 years post-menopause, data do not demonstrate convincing cardiovascular protective benefit in any age group. Premature menopause is associated with elevated future risk of diverse cardiovascular diseases. Further studies are needed to further elucidate mechanisms and identify novel preventive strategies.

The effects of estrogen and hormonereplacement therapy on cardiovascular systems.

Postmenopausal women have an increased risk of cardiovascular disease, which is believed to correlate with lower estrogen level. There are conflicting data regarding hormonereplacement therapy (HRT) based on the timing of this therapy. After large randomized trials showed no cardiovascular benefit of hormone replacement, estrogen replacement therapy was dramatically reduced even though starting hormone replacement in early postmenopausal period had shown significant benefit. There are hardly any reviews discussing in detail the effect of HRT on cardiovascular system while briefly discussing other effects of this therapy in postmenopausal women. The novelty of this review is the comprehensive discussion of this effect that can help researchers and clinicians to design future research or trials. In this manuscript, the effect of HRT on cardiovascular system in clinical trials and basic science will be reported and potentially erroneous conclusions drawn by various studies will be discussed. Furthermore, various noncardiovascular effect of HRT will be analyzed.

LBA19 GEICAM/2014-12 (FLIPPER) study: First analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC)

LBA19 GEICAM/2014-12 (FLIPPER) study: First analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC)

The Effectiveness of Prasterone vs Placebo Therapy as the Vulvovaginal Atrophy Treatment in Menopausal Women: Meta-Analysis

Background : Vulvovaginal atrophy is a condition that often occurs in menopausal women due to Estrogen decreased. Prasterone (DHEA) is a steroid hormone that can be converted into Estrogen in the target tissue. Objective : This paper aims to evaluate the effectiveness of administering Prasterone as Vulvovaginal Atrophy therapy in menopausal women. Methods : A systematic data search was performed on a medical database (PUBMED, Google scholar, Cochrane). Inclusion criteria: (1) randomized study of Prasterone as Vulvovaginal Atrophy therapy in postmenopausal women, (2) all-inclusive papers can be accessed completely, and (3) the data obtained can be accurately analysed. Results: Three RCTs with a total of 696 patients were analysed. The average number of Superficial Cells (mean difference [MD] 7.63, and 95% [CI] 7.57 to 7.70 (P &lt;0.00001). The average number of Parabasal Cells (mean difference [MD] -29.84, and 95% [CI] -30.25 to -29.44 (P &lt;0.00001). The average number of vaginal pH (mean difference [MD] -0.69, and 95% [CI] -0.70 to -0.68 (P &lt;0.00001). The average number of Dyspareunia (mean difference [MD] -0.38, and 95% [CI] -0.39 to -0.37 (P &lt;0.00001). All diamonds do not intersect the vertical line, and have p &lt;0.05, it proves that there are significant differences between the two groups. All non-hysterectomized women have an atrophic or inactive endometrium. Side effects that are often complained of is headache and application site discharge. Conclusion This meta-analysis concludes that Prasterone therapy has a significant therapeutic effect for Vulvovaginal Atrophy in menopausal women

Estradiol Replacement at the Critical Period Protects Hippocampal Neural Stem Cells to Improve Cognition in APP/PS1 Mice

It has been suggested that there is a critical window for estrogen replacement therapy (ERT) in postmenopausal women with Alzheimer’s disease (AD); however, supporting evidence is lacking. To address this issue, we investigated the effective period for estradiol (E2) treatment using a mouse model of AD. Four-month-old female APPswe/PSEN1dE9 (APP/PS1) mice were ovariectomized (OVX) and treated with E2 for 2 months starting at the age of 4 months (early period), 6 months (mid-period), or 8 months (late period). We then evaluated hippocampal neurogenesis, β-amyloid (Aβ) accumulation, telomerase activity, and hippocampal-dependent behavior. Compared to age-matched wild type mice, APP/PS1 mice with intact ovaries showed increased proliferation of hippocampal neural stem cells (NSCs) at 8 months of age and decreased proliferation of NSCs at 10 months of age; meanwhile, Aβ accumulation progressively increased with age, paralleling the reduced survival of immature neurons. OVX-induced depletion of E2 in APP/PS1 mice resulted in elevated Aβ levels accompanied by elevated p75 neurotrophin receptor (p75NTR) expression and increased NSC proliferation at 6 months of age, which subsequently declined; accelerated reduction of immature neurons starting from 6 months of age, and reduced telomerase activity and worsened memory performance at 10 months of age. Treatment with E2 in the early period post-OVX, rather than in the mid or late period, abrogated these effects, and p75NTR inhibition reduced the overproliferation of NSCs in 6-month-old OVX-APP/PS1 mice. Thus, E2 deficiency in young APP/PS1 mice exacerbates cognitive deficits and depletes the hippocampal NSC pool in later life; this can be alleviated by E2 treatment in the early period following OVX, which prevents Aβ/p75NTR-induced NSC overproliferation and preserves telomerase activity.

Urinary tract infections in the elderly: a review of disease characteristics and current treatment options.

Urinary tract infections (UTIs) are common in the elderly, and cover a range of conditions from asymptomatic bacteriuria to urosepsis. Risk factors for developing symptomatic UTIs include immunosenescence, exposure to nosocomial pathogens, multiple comorbidities, and a history of UTIs. European guidelines on urological infections recommend antimicrobial treatment only for symptomatic UTIs. Non-antimicrobial options to treat and prevent UTIs include among others cranberry products, OM-89 Escherichia coli bacterial lysate vaccine, and estrogen therapy in postmenopausal women, although evidence for their efficacy is weak. Another non-antimicrobial option to control and prevent UTIs is a medical device (Utipro Plus®) containing xyloglucan, gelatin, propolis, and extracts of Hibiscus sabdariffa. The device acts in the intestine as a mechanical barrier to protect against invasion by uropathogenic E. coli strains. A randomized controlled trial of Utipro Plus® in patients with uncomplicated UTIs provided good-quality evidence of its efficacy compared with placebo. In an observational study of Utipro Plus® in patients with recurrent UTIs, more than 80% women reported a return to their pre-UTI clinical status and about 30% transitioned from symptomatic UTIs to asymptomatic bacteriuria. New treatment strategies that offer a safe and effective non-antimicrobial means of managing UTIs could have an important role in the elderly.

Romosozumab and Sequential Therapy in Postmenopausal Osteoporosis.

OBJECTIVE: To review and summarize studies on the effects of romosozumab as sequential therapy for improvements in bone turnover markers, bone mineral density (BMD), and clinical fracture in postmenopausal (PMP) women.<br/> DATA SOURCES: A search of PubMed (1966-August 2019) and International Pharmaceutical Abstracts (1970-August 2019) was conducted using the MeSH and key word term romosozumab and limited to controlled clinical trials.<br/> STUDY SELECTION AND DATA EXTRACTION: An initial review yielded 12 articles. Articles that did not evaluate use of romosozumab before or after another osteoporosis treatment were excluded. Five articles that evaluated the effects of sequential treatment with romosozumab in PMP women on bone turnover markers, bone mineral density, and fracture were included in the final review.<br/> DATA SYNTHESIS: Romosozumab is a humanized, monoclonal antibody that increases bone formation and reduces bone resorption via inhibition of sclerostin. This inhibition stimulates signaling pathways resulting in increased bone formation, reduced bone resorption and increases in BMD. Romosozumab is indicated for the treatment of osteoporosis in PMP women who are at high risk for fracture and failed or cannot take other treatments. The current evidence describing the controlled clinical trials that evaluated use of romosozumab in sequence with other therapies for treatment of PMP osteoporosis is summarized.<br/> CONCLUSION: An evaluation of studies where romosozumab was used in sequence to other therapies in PMP women showed that it causes significant reductions in bone resorption markers, increases in bone-formation markers, improves BMD, and reduces the risk of clinical fracture. However, these efficacy improvements must be carefully weighed against the increased risk of cardiovascular adverse effects compared with other treatments.

Romosozumab and Sequential Therapy in Postmenopausal Osteoporosis

OBJECTIVE: To review and summarize studies on the effects of romosozumab as sequential therapy for improvements in bone turnover markers, bone mineral density (BMD), and clinical fracture in postmenopausal (PMP) women.<br/> DATA SOURCES: A search of PubMed (1966-August 2019) and International Pharmaceutical Abstracts (1970-August 2019) was conducted using the MeSH and key word term romosozumab and limited to controlled clinical trials.<br/> STUDY SELECTION AND DATA EXTRACTION: An initial review yielded 12 articles. Articles that did not evaluate use of romosozumab before or after another osteoporosis treatment were excluded. Five articles that evaluated the effects of sequential treatment with romosozumab in PMP women on bone turnover markers, bone mineral density, and fracture were included in the final review.<br/> DATA SYNTHESIS: Romosozumab is a humanized, monoclonal antibody that increases bone formation and reduces bone resorption via inhibition of sclerostin. This inhibition stimulates signaling pathways resulting in increased bone formation, reduced bone resorption and increases in BMD. Romosozumab is indicated for the treatment of osteoporosis in PMP women who are at high risk for fracture and failed or cannot take other treatments. The current evidence describing the controlled clinical trials that evaluated use of romosozumab in sequence with other therapies for treatment of PMP osteoporosis is summarized.<br/> CONCLUSION: An evaluation of studies where romosozumab was used in sequence to other therapies in PMP women showed that it causes significant reductions in bone resorption markers, increases in bone-formation markers, improves BMD, and reduces the risk of clinical fracture. However, these efficacy improvements must be carefully weighed against the increased risk of cardiovascular adverse effects compared with other treatments.

Response to neoadjuvant chemotherapy and the 21-gene breast recurrence score in young women with estrogen receptor-positive early breast cancer.

514 Background: The 21- gene Breast Recurrence Score predicts benefit from adjuvant chemotherapy in estrogen receptor positive (ER+), HER-2 negative (-) breast cancer (BC). We aimed to examine whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NAC). Methods: We identified patients with stage I-III ER+/HER2− BC treated with NAC from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤ 40 years. The 21-gene assay was performed on tumor specimens removed prior to NAC either as part of clinical care or retrospectively for research. Pathologic complete response (pCR) was defined as no residual invasive tumor (ypT0/is ypN0). The relationship between Recurrence Score result (RS) and pCR was evaluated using logistic regression modeling. Results: 76 women in the cohort had undergone NAC for ER+, HER2- BC and were eligible for this analysis: 5 had undergone clinical 21-gene assay testing, 71 had banked specimens retrospectively tested. Median age at diagnosis was 36.7 (24.3-40). Most tumors were of ductal histology (78%), high grade (51%), progesterone receptor (PgR) positive (86%), ≥T2 (88%), clinically node positive (74%), and anthracycline and taxane containing protocols were administered in 86% of cases. RS ranged between 5-75 with 50% &gt; 25 and only 4 &lt; 11. Mean RS was significantly higher among tumors achieving pCR vs. non-pCR response (51.9 vs. 26.6, pwilcoxon= 0.0005). pCR rate in patients with RS &gt; 25 was 21% (8/38) vs. 5% in patients with RS &lt; 25 (2/38), with both pCRs in the &lt;25 group in patients with RS 21-25. In univariable analysis, PgR negativity (odds ratio (OR) 5.62, 95% confidence interval (CI) 1.27-24.89, p = 0.02), high grade (OR 9.03, 95%CI 1.07-76.32, p = 0.04) and higher RS as a continuous variable (OR 1.08, 95%CI 1.04-1.13, p = 0.0003) were associated with a greater likelihood of pCR. In multivariable analysis only RS remained significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01): a 7% increase in the odds of pCR for every 1-point increase in RS. Conclusions: In young women with ER+, HER2- BC who received NAC, higher pretreatment RS was associated with an increased likelihood of pCR. Genomic expression profiling assays may have a role in decision-making in young women in need of neoadjuvant therapy. For women with low likelihood of benefiting from NAC, alternative approaches are clearly warranted. Given the demonstrated efficacy of neoadjuvant endocrine therapy in post-menopausal women, further evaluation in young women should be pursued.

Aging Reduces Estradiol Protection Against Neural but Not Metabolic Effects of Obesity in Female 3xTg-AD Mice.

Vulnerability to Alzheimer’s disease (AD) is increased by several risk factors, including midlife obesity, female sex, and the depletion of estrogens in women as a consequence of menopause. Conversely, estrogen-based hormone therapies have been linked with protection from age-related increases in adiposity and dementia risk, although treatment efficacy appears to be affected by the age of initiation. Potential interactions between obesity, AD, aging, and estrogen treatment are likely to have significant impact on optimizing the use of hormone therapies in postmenopausal women. In the current study, we compared how treatment with the primary estrogen, 17β-estradiol (E2), affects levels of AD-like neuropathology, behavioral impairment, and other neural and systemic effects of preexisting diet-induced obesity in female 3xTg-AD mice. Importantly, experiments were conducted at chronological ages associated with both the early and late stages of reproductive senescence. We observed that E2 treatment was generally associated with significantly improved metabolic outcomes, including reductions in body weight, adiposity, and leptin, across both age groups. Conversely, neural benefits of E2 in obese mice, including decreased β-amyloid burden, improved behavioral performance, and reduced microglial activation, were observed only in the early aging group. These results are consistent with the perspective that neural benefits of estrogen-based therapies require initiation of treatment during early rather than later phases of reproductive aging. Further, the discordance between E2 protection against systemic versus neural effects of obesity across age groups suggests that pathways other than general metabolic function, perhaps including reduced microglial activation, contribute to the mechanism(s) of the observed E2 actions. These findings reinforce the potential systemic and neural benefits of estrogen therapies against obesity, while also highlighting the critical role of aging as a mediator of estrogens’ protective actions.

Effectiveness of Cognitive Therapy in Post-Menopausal Women

Objective: To find the effectiveness of cognitive therapy in post-menopausal women. Method: The study group consisted of 50 post-menopausal women, aged between 45-65 years, screening of 100 women was done and 50 women having cognitive changes and fulfilling the inclusion and exclusion criteria were selected. They were given exercises for 4 weeks,4 times per week and pre-post result were calculated on the basis of attention, memory, anxiety and depression. The scores were measured by using mini mental scale, mood scale and Hamilton depression rating scale. Conclusion: The results demonstrated that there is statistically extremely significant difference in cognitive changes in post menopausal women. (p &gt;0.0001)

FDA Approval Summary: Palbociclib for Male Patients with Metastatic Breast Cancer.

On April 4, 2019, the FDA approved a supplemental new drug application for palbociclib (IBRANCE), to expand the approved indications in women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant, to include men. Palbociclib was first approved in 2015 for use in combination with letrozole for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women and subsequently in 2016 in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. The current approval was primarily based on the results of the PALOMA-2 and PALOMA-3 trials and, supported by real-world data from electronic health records and insurance claims. To support the safety evaluation in male patients, data from two phase I studies with palbociclib and safety information from the global safety database, were also reviewed. This article summarizes FDA decision-making and data supporting the approval of palbociclib for the treatment of male patients with HR-positive, HER2-negative advanced or MBC.